PUBLICATION

An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia

Authors
Benet-Pages, A., Orlik, P., Strom, T.M., and Lorenz-Depiereux, B.
ID
ZDB-PUB-050203-6
Date
2005
Source
Human molecular genetics   14(3): 385-390 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Amino Acid Sequence
  • Calcinosis/complications
  • Calcinosis/genetics*
  • Cell Line
  • Cells, Cultured
  • Child
  • Fibroblast Growth Factors/blood
  • Fibroblast Growth Factors/genetics*
  • Fibroblast Growth Factors/metabolism
  • Homeostasis
  • Humans
  • Hypophosphatemia, Familial/complications
  • Hypophosphatemia, Familial/genetics*
  • Male
  • Molecular Sequence Data
  • Mutation, Missense
  • N-Acetylgalactosaminyltransferases/genetics
  • Neoplasm Proteins/genetics
  • Phenotype
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
PubMed
15590700 Full text @ Hum. Mol. Genet.
Abstract
Familial tumoral calcinosis (FTC) is an autosomal recessive disorder characterized by ectopic calcifications and elevated serum phosphate levels. Recently, mutations in the GALNT3 gene have been described to cause FTC. The FTC phenotype is regarded as the metabolic mirror image of hypophosphatemic conditions, where causal mutations are known in genes FGF23 or PHEX. We investigated an individual with FTC who was negative for GALNT3 mutations. Sequencing revealed a homozygous missense mutation in the FGF23 gene (p.S71G) at an amino acid position which is conserved from fish to man. Wild-type FGF23 is secreted as intact protein and processed N-terminal and C-terminal fragments. Expression of the mutated protein in HEK293 cells showed that only the C-terminal fragment is secreted, whereas the intact protein is retained in the Golgi complex. In addition, determination of circulating FGF23 in the affected individual showed a marked increase in the C-terminal fragment. These results suggest that the FGF23 function is decreased by absent or extremely reduced secretion of intact FGF23. We conclude that FGF23 mutations in hypophosphatemic rickets and FTC have opposite effects on phosphate homeostasis.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping